Implantable systems and methods for monitoring BNP levels, HF and MI

ABSTRACT

Methods for monitoring a patient&#39;s level of B-type natriuretic peptide (BNP), and implantable cardiac systems capable of performing such methods, are provided. A ventricle is paced for a period of time to provoke a ventricular evoked response, and a ventricular intracardiac electrogram (IEGM) indicative of the ventricular evoked response is obtained. Based on the ventricular IEGM, there is a determination of at least one ventricular evoked response metric (e.g., ventricular evoked response peak-to-peak amplitude, ventricular evoked response area and/or ventricular evoked response maximum slope), and the patient&#39;s level of BNP is monitored based on determined ventricular evoked response metric(s). Based on the monitored level&#39;s of BNP, the patients heart failure (HF) condition and/or risks and/or occurrences of certain events (e.g., an acute HF exacerbation and/or an acute myocardial infarction) can be monitored.

PRIORITY CLAIM

This application is a Divisional application of and claims priority andother benefits from U.S. patent application Ser. No. 12/341,074, filedDec. 22, 2008, entitled “IMPLANTABLE SYSTEMS AND METHODS FOR MONITORINGBNP LEVELS, HF AND MI”, now U.S. Pat. No. 8,326,422, incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

Embodiments of the present invention relate to implantable cardiacsystems, and methods for use therewith.

BACKGROUND

B-type natriuretic peptide (BNP) is a 32-amino-acid polypeptide secretedby the ventricles of the heart in response to excessive stretching ofmyocytes (heart muscles cells) in the ventricles. The levels of BNP aretypically elevated in patients with left ventricular dysfunction.Further, BNP levels correlate with both the severity of symptoms and theprognosis in congestive heart failure. Additionally, BNP appears to be auseful marker of cardiovascular risk, even in people with no clinicalevidence of cardiovascular disease.

Levels of BNP are typically measured based on blood samples. Forexample, 5 mL of blood can be collected into a tube containing potassiumEDTA, and the level of BNP can be measured using a Triage™ BNP Testavailable from Biosite Inc. of San Diego, Calif. However, because mosttechniques for measuring levels of BNP require blood samples, they arenot practical for chronic monitoring of levels of BNP. Nevertheless, itwould be advantageous if systems and methods were available forproviding chronic monitoring of levels of BNP.

Heart failure (HF) is a condition in which a patient's heart works lessefficiently than it should, resulting in the heart failing to supply thebody sufficiently with the oxygen rich blood it requires, either atexercise or at rest. Congestive heart failure (CHF) is heart failureaccompanied by a build-up of fluid pressure in the pulmonary bloodvessels that perfuse the lungs.

Chronic diseases such as CHF require close medical management to reducemorbidity and mortality. Because the disease status evolves with time,frequent physician follow-up examinations are typically necessary. Atfollow-up, the physician may make adjustments to the drug regimen inorder to optimize therapy. This conventional approach of periodicfollow-up is unsatisfactory for some diseases, such as CHF, in whichacute, life-threatening exacerbations can develop between physicianfollow-up examinations. Accordingly, it would be advantageous if systemsand methods were available for providing chronic monitoring of apatient's HF condition.

Myocardial infraction (MI) (also known as a heart attack) is the deathof heart muscle from the sudden blockage of a coronary artery by a bloodclot. Coronary arteries are blood vessels that supply the heart musclewith blood and oxygen. Blockage of a coronary artery deprives the heartmuscle of blood and oxygen, causing injury to the heart muscle. Injuryto the heart muscle causes chest pain and chest pressure sensation. Ifblood flow is not restored to the heart muscle within 20 to 40 minutes,irreversible death of the heart muscle will begin to occur. Musclecontinues to die for six to eight hours at which time the heart attackusually is “complete.” The dead heart muscle is eventually replaced byscar tissue. When an MI occurs, it is important that treatment beprovide to the patient as soon as possible, so that sustained damage tothe patient's heart can be prevented. However, some MIs are silent,meaning they are non-symptomatic, and thus a patient may be unaware thatan MI occurred. Further, even if a MI is symptomatic, a patient may notbe in a condition that they can notify a physician of the MI.

A goal of the management in of MI is to salvage as much myocardium aspossible during the acute phase of MI to prevent further complications.This is because as time passes, the risk of damage to the heart muscleincreases. Accordingly, it would be useful if systems and methods wereavailable for chronically monitoring for acute MIs, and risks thereof.

SUMMARY

Certain embodiments of the present invention relate to methods formonitoring a patient's level of BNP, and implantable cardiac systemscapable of performing such methods. In accordance with an embodiment, aventricle is paced for a period of time to provoke a ventricular evokedresponse, and a ventricular intracardiac electrogram (IEGM) indicativeof the ventricular evoked response is obtained. Based on the ventricularIEGM, there is a determination of at least one ventricular evokedresponse metric, and the patient's level of BNP is monitored based onthat determined ventricular evoked response metric(s). Exemplaryventricular evoked response metrics include, but are not limited to,ventricular evoked response peak-to-peak amplitude, ventricular evokedresponse area and ventricular evoked response maximum slope.

In the manner described above, the ventricular evoked response metric(s)can be determined from time to time (e.g., at different times thatventricular automatic capture threshold detection is performed), so thatthe patient's level of BNP and/or changes therein, can be monitored overtime.

In accordance with specific embodiments, the monitoring of the patient'slevel of BNP includes estimating a value for the patient's level of BNPbased on the determined ventricular evoked response metric(s), e.g.,using a quadratic or higher order polynomial equation, but not limitedthereto.

In accordance with specific embodiments, a patient's heart failure (HF)condition can be monitored based on the monitored level of BNP, whichis/are monitored based on ventricular evoked response metric(s). Thiscan include detecting a worsening of the patient's HF condition if themonitored level of BNP increases, and detecting an improvement of thepatient's HF condition if the monitored level of BNP decreases.Additionally, or alternatively, an impending acute HF exacerbation canbe predicted based on whether an estimated value of the level of BNPexceeds a threshold, and/or an acute HF exacerbation can be detectedbased on whether an estimated value of the level of BNP exceeds athreshold. Monitoring a patient's HF condition can also includingmonitoring changes in the patient's HF condition by monitored changes inthe patient's level of BNP.

In accordance with specific embodiments, monitoring for an impendingacute MI and/or detection of an acute MI can be performed based on themonitored level of BNP, which is/are monitored based on ventricularevoked response metric(s). This can include detecting an increase inrisk of an acute MI if the monitored level of BNP increases, anddetecting a decrease in risk of an acute MI if the monitored level ofBNP decreases. Additionally, or alternatively, an impending acute MI canbe predicted based on whether the monitored level of BNP exceeds athreshold, and/or an occurrence of an acute MI can be detected based onwhether an estimated value of the level of BNP exceeds a threshold.Further, changes in a patient's risk of an acute Ml can be monitored bymonitoring changes in the patient's level of BNP.

Other embodiments of the present invention can be used to select apreferred ventricular pacing energy level. This can include, determininga ventricular capture threshold for pacing a ventricle, and determining,based on the ventricular capture threshold, a first ventricular pacingenergy level that provides for reliable capture of the ventricle. Forexample, the first ventricular pacing energy level can be determined byadding a safety margin, a working margin or some other margin to thedetermined ventricular capture threshold. At least one ventricularevoked response metric is determined for one or more ventricular evokedresponse that occurs in response to ventricular pacing at the firstventricular pacing energy level. Additionally, at least one ventricularevoked response is determined for one or more ventricular evokedresponse that occurs in response to ventricular pacing at one or moreenergy level greater than the first ventricular pacing energy level. Apreferred ventricular pacing energy level to use for ventricular pacingis selected based on the ventricular evoked response metrics determinedfor the various pacing energy levels. This can include selecting aventricular pacing energy level greater than the first ventricularpacing energy level as the preferred ventricular pacing energy level, ifusing the energy level greater than the first ventricular pacing energylevel provides at least one of the following: a reduction in thepatient's level of BNP, an improved HF condition, a reduction in thepatient's risk of an acute HF exacerbation, and/or a reduction in thepatient's risk of an acute myocardial infarction.

This summary is not intended to be a complete description of, or limitthe scope of, the invention. Alternative and additional features,aspects, and objects of the invention can be obtained from a review ofthe specification, the figures, and the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a simplified, partly cutaway view illustrating an implantablestimulation device in electrical communication with at least three leadsimplanted into a patient's heart for delivering multi-chamberstimulation and shock therapy and sensing cardiac activity.

FIG. 2 is a functional block diagram of the multi-chamber implantablestimulation device of FIG. 1, illustrating the basic elements thatprovide pacing stimulation, cardioversion, and defibrillation in fourchambers of the heart.

FIG. 3 is a high level flow diagram that is used to summarize specificembodiments of the present invention that can be used to monitor apatient's level of BNP and monitor changes in a patient's level of BNP,as well as to perform HF and/or MI monitoring based on the monitoredlevels of BNP.

FIG. 4 is a high level flow diagram that is used to summarize specificembodiments of the present invention that can be used to select a pacingenergy level taking into account whether an increased energy levelresults in a reduction in level of BNP, an improved HF condition, areduced risk of an acute HF exacerbation and/or reduced risk of an acuteMI.

DETAILED DESCRIPTION

The following description is of the best modes presently contemplatedfor practicing various embodiments of the present invention. Thisdescription is not to be taken in a limiting sense but is made merelyfor the purpose of describing the general principles of the invention.The scope of the invention should be ascertained with reference to theissued claims. In the description of the invention that follows, likenumerals or reference designators will be used to refer to like parts orelements throughout.

Exemplary Implantable System

Referring to FIG. 1, an exemplary chronically implantable device 110(also referred to as a pacing device, a pacing apparatus, a stimulationdevice, or simply a device) is in electrical communication with apatient's heart 112 by way of three leads, 120, 124 and 130, suitablefor delivering multi-chamber stimulation. The device and the leads shalloften be referred to hereafter collectively as a chronically implantablesystem. While not necessary to perform embodiments of the presentinvention, the exemplary device 110 is also capable of delivering shocktherapy.

To sense atrial cardiac signals and to provide right atrial chamberstimulation, the stimulation device 110 is coupled to an implantableright atrial lead 120 having at least an atrial tip electrode 122, whichtypically is implanted in the patient's right atrial appendage. To senseleft atrial and ventricular cardiac signals and to provide left-chamberpacing therapy, the stimulation device 110 is coupled to a “coronarysinus” lead 124 designed for placement in the “coronary sinus region”via the coronary sinus for positioning a distal electrode adjacent tothe left ventricle and/or additional electrode(s) adjacent to the leftatrium. As used herein, the phrase “coronary sinus region” refers to thevasculature of the left ventricle, including any portion of the coronarysinus, great cardiac vein, left marginal vein, left posteriorventricular vein, middle cardiac vein, and/or small cardiac vein or anyother cardiac vein accessible by the coronary sinus.

Accordingly, an exemplary coronary sinus lead 124 is designed to receiveleft atrial and ventricular cardiac signals and to deliver left atrialand ventricular pacing therapy using at least a left ventricular tipelectrode 126, left atrial pacing therapy using at least a left atrialring electrode 127, and shocking therapy using at least a left atrialcoil electrode 128. The present invention may of course be practicedwith a coronary sinus lead that does not include left atrial sensing,pacing or shocking electrodes.

The stimulation device 110 is also shown in electrical communicationwith the patient's heart 112 by way of an implantable right ventricularlead 130 having, in this embodiment, a right ventricular tip electrode132, a right ventricular ring electrode 134, a right ventricular (RV)coil electrode 136, and an SVC coil electrode 138. Typically, the rightventricular lead 130 is transvenously inserted into the heart 112 so asto place the right ventricular tip electrode 132 in the rightventricular apex so that the RV coil electrode 136 will be positioned inthe right ventricle and the SVC coil electrode 138 will be positioned inthe superior vena cava. Accordingly, the right ventricular lead 130 iscapable of receiving cardiac signals and delivering stimulation in theform of pacing and shock therapy to the right ventricle. It will beunderstood by those skilled in the art that other lead and electrodeconfigurations such as epicardial leads and electrodes may be used inpracticing the invention. More generally, electrodes may be positionedendocardially, epicardially or pericardially.

As illustrated in FIG. 2, a simplified block diagram is shown of themulti-chamber implantable implantable device 110, which is capable oftreating both fast and slow arrhythmias with stimulation therapy,including pacing, cardioversion and defibrillation stimulation. While aparticular multi-chamber device is shown, this is for illustrationpurposes only, and one of skill in the art could readily duplicate,eliminate or disable the appropriate circuitry in any desiredcombination to provide a device capable of treating the appropriatechamber(s) with pacing, cardioversion and defibrillation stimulation.

The housing 240 for the implantable device 110, shown schematically inFIG. 2, is often referred to as the “can”, “case” or “case electrode”and may be programmably selected to act as the return electrode for all“unipolar” modes. The housing 240 may further be used as a returnelectrode alone or in combination with one or more of the coilelectrodes, 128, 136 and 138, for shocking purposes. The housing 240further includes a connector (not shown) having a plurality ofterminals, 242, 244, 246, 248, 252, 254, 256, and 258 (shownschematically and, for convenience, the names of the electrodes to whichthey are connected are shown next to the terminals). As such, to achieveright atrial sensing and pacing, the connector includes at least a rightatrial tip terminal (A_(R) TIP) 242 adapted for connection to the atrialtip electrode 122.

To achieve left atrial and ventricular sensing, pacing and shocking, theconnector includes at least a left ventricular tip terminal (V_(L) TIP)244, a left atrial ring terminal (A_(L) RING) 246, and a left atrialshocking terminal (A_(L) COIL) 248, which are adapted for connection tothe left ventricular tip electrode 126, the left atrial ring electrode127, and the left atrial coil electrode 128, respectively.

To support right ventricle sensing, pacing and shocking, the connectorfurther includes a right ventricular tip terminal (V_(R) TIP) 252, aright ventricular ring terminal (V_(R) RING) 254, a right ventricularshocking terminal (R_(V) COIL) 256, and an SVC shocking terminal (SVCCOIL) 258, which are adapted for connection to the right ventricular tipelectrode 132, right ventricular ring electrode 134, the RV coilelectrode 136, and the SVC coil electrode 138, respectively.

At the core of the implantable device 110 is a programmablemicrocontroller 260 which controls the various types and modes ofstimulation therapy. As is well known in the art, the microcontroller260 typically includes a microprocessor, or equivalent controlcircuitry, designed specifically for controlling the delivery ofstimulation therapy and can further include RAM or ROM memory, logic andtiming circuitry, state machine circuitry, and I/O circuitry. Typically,the microcontroller 260 includes the ability to process or monitor inputsignals (data) as controlled by a program code stored in a designatedblock of memory. The details of the design of the microcontroller 260are not critical to the present invention. Rather, any suitablemicrocontroller 260 can be used to carry out the functions describedherein. The use of microprocessor-based control circuits for performingtiming and data analysis functions are well known in the art. Inspecific embodiments of the present invention, the microcontroller 260performs some or all of the steps associated with arrhythmia detectionand myocardial ischemia detection.

Representative types of control circuitry that may be used with theinvention include the microprocessor-based control system of U.S. Pat.No. 4,940,052 (Mann et. al.) and the state-machines of U.S. Pat. No.4,712,555 (Sholder) and U.S. Pat. No. 4,944,298 (Sholder). For a moredetailed description of the various timing intervals used within thepacing device and their inter-relationship, see U.S. Pat. No. 4,788,980(Mann et. al.). The '052, '555, '298 and '980 patents are incorporatedherein by reference.

An atrial pulse generator 270 and a ventricular pulse generator 272generate pacing stimulation pulses for delivery by the right atrial lead120, the right ventricular lead 130, and/or the coronary sinus lead 124via an electrode configuration switch 274. It is understood that inorder to provide stimulation therapy in each of the four chambers of theheart, the atrial and ventricular pulse generators, 270 and 272, mayinclude dedicated, independent pulse generators, multiplexed pulsegenerators, or shared pulse generators. The pulse generators, 270 and272, are controlled by the microcontroller 260 via appropriate controlsignals, 276 and 278, respectively, to trigger or inhibit thestimulation pulses.

The microcontroller 260 further includes timing control circuitry 279which is used to control pacing parameters (e.g., the timing ofstimulation pulses) as well as to keep track of the timing of refractoryperiods, noise detection windows, evoked response windows, alertintervals, marker channel timing, etc., which is well known in the art.Examples of pacing parameters include, but are not limited to,atrio-ventricular delay, interventricular delay and interatrial delay.

The switch bank 274 includes a plurality of switches for connecting thedesired electrodes to the appropriate I/O circuits, thereby providingcomplete electrode programmability. Accordingly, the switch 274, inresponse to a control signal 280 from the microcontroller 260,determines the polarity of the stimulation pulses (e.g., unipolar,bipolar, etc.) by selectively closing the appropriate combination ofswitches (not shown) as is known in the art.

Atrial sensing circuits 282 and ventricular sensing circuits 284 mayalso be selectively coupled to the right atrial lead 120, coronary sinuslead 124, and the right ventricular lead 130, through the switch 274 fordetecting the presence of cardiac activity in each of the four chambersof the heart. Accordingly, the atrial (ATR. SENSE) and ventricular (VTR.SENSE) sensing circuits, 282 and 284, may include dedicated senseamplifiers, multiplexed amplifiers, or shared amplifiers. The switch 274determines the “sensing polarity” of the cardiac signal by selectivelyclosing the appropriate switches, as is also known in the art. In thisway, the clinician may program the sensing polarity independent of thestimulation polarity.

Each sensing circuit, 282 and 284, preferably employs one or more lowpower, precision amplifiers with programmable gain and/or automatic gaincontrol, bandpass filtering, and a threshold detection circuit, as knownin the art, to selectively sense the cardiac signal of interest. Theautomatic gain control enables the device 110 to deal effectively withthe difficult problem of sensing the low amplitude signalcharacteristics of atrial or ventricular fibrillation. Such sensingcircuits, 282 and 284, can be used to determine cardiac performancevalues used in the present invention. Alternatively, an automaticsensitivity control circuit may be used to effectively deal with signalsof varying amplitude.

The outputs of the atrial and ventricular sensing circuits, 282 and 284,are connected to the microcontroller 260 which, in turn, are able totrigger or inhibit the atrial and ventricular pulse generators, 270 and272, respectively, in a demand fashion in response to the absence orpresence of cardiac activity, in the appropriate chambers of the heart.The sensing circuits, 282 and 284, in turn, receive control signals oversignal lines, 286 and 288, from the microcontroller 260 for purposes ofmeasuring cardiac performance at appropriate times, and for controllingthe gain, threshold, polarization charge removal circuitry (not shown),and timing of any blocking circuitry (not shown) coupled to the inputsof the sensing circuits, 282 and 286. The sensing circuits can be usedto acquire IEGM signals, which can be used to measure ventricular evokedresponse metrics, in accordance with embodiments of the presentinvention.

For arrhythmia detection, the device 110 includes an arrhythmia detector262 that utilizes the atrial and ventricular sensing circuits, 282 and284, to sense cardiac signals to determine whether a rhythm isphysiologic or pathologic. The timing intervals between sensed events(e.g., P-waves, R-waves, and depolarization signals associated withfibrillation) are then classified by the microcontroller 260 bycomparing them to a predefined rate zone limit (i.e., bradycardia,normal, low rate VT, high rate VT, and fibrillation rate zones) andvarious other characteristics (e.g., sudden onset, stability,physiologic sensors, and morphology, etc.) in order to assist withdetermining the type of remedial therapy that is needed (e.g.,bradycardia pacing, anti-tachycardia pacing, cardioversion shocks ordefibrillation shocks, collectively referred to as “tiered therapy”).The arrhythmia detector 262 can be implemented within themicrocontroller 260, as shown in FIG. 2. Thus, this detector 262 can beimplemented by software, firmware, or combinations thereof. It is alsopossible that all, or portions, of the arrhythmia detector 262 can beimplemented using hardware. Further, it is also possible that all, orportions, of the arrhythmia detector 262 can be implemented separatefrom the microcontroller 260.

In accordance with embodiments of the present invention, the implantabledevice 110 includes a ventricular evoked response monitor 263, that canmeasure ventricular evoked response metrics (i.e., metrics of pacedR-waves) of ventricular IEGMs obtained, e.g., using the rightventricular lead 130, but not limited thereto. The ventricular evokedresponse monitor 263 can be implemented within the microcontroller 260,as shown in FIG. 2. Thus, the ventricular evoked response monitor 263can be implemented by software, firmware, or combinations thereof. It isalso possible that all, or portions, of the monitor 263 can beimplemented using hardware. Further, it is also possible that all, orportions, of the ventricular evoked response monitor 263 can beimplemented separate from the microcontroller 260. As the term is usedherein, a ventricular evoked response is an electrical signal arisingfrom ventricular cardiac tissue depolarization in response to deliveryof a ventricular pacing pulse. Stated another way, a ventricular evokedresponse is a paced ventricular event. The ventricular evoked responsemonitor 263 can be used to perform step 306, discussed below withreference to FIG. 3.

In accordance with embodiments of the present invention, the implantabledevice 110 also includes a B-type natriuretic peptide (BNP) monitor 264,that monitors a patient's level of BNP using embodiments of the presentinvention, which are described in detail below. The BNP monitor 264 canbe implemented within the microcontroller 260, as shown in FIG. 2. Thus,the BNP monitor 264 can be implemented by software, firmware, orcombinations thereof. It is also possible that all, or portions, of theBNP monitor 264 can be implemented using hardware. Further, it is alsopossible that all, or portions, of the monitor 264 can be implementedseparate from the microcontroller 260. The BNP monitor 264 can include,or communicate with, a component (e.g., ventricular evoked responsemonitor) that measures ventricular evoked response metrics of aventricular IEGM. The BNP monitor 264 can be used to perform step 308,discussed below with reference to FIG. 3.

In accordance with embodiments of the present invention, the implantabledevice 110 also includes a heart failure (HF) monitor 265, that monitorsa patient's heart failure condition using embodiments of the presentinvention, which are described in detail below. The HF monitor 265 canbe implemented within the microcontroller 260, as shown in FIG. 2. Thus,the HF monitor 265 can be implemented by software, firmware, orcombinations thereof. It is also possible that all, or portions, of themonitor 265 can be implemented using hardware. Further, it is alsopossible that all, or portions, of the HF monitor 265 can be implementedseparate from the microcontroller 260. The HF monitor 265 can include,or communicate with, a component (e.g., the BNP monitor 264) thatmonitors levels of BNP. The HF monitor 265 can be used to perform step310, discussed below with reference to FIG. 3.

The implantable device 110 is also shown as including a myocardialinfarction (MI) monitor 266 and a pacing energy level selector 268. TheMI monitor 266 can predict an impeding acute MI and/or detect anoccurrence of an acute MI, in accordance with embodiments of the presentinvention described below. The pacing energy level selector 268 canselect a preferred ventricular pacing energy level, in accordance withembodiments of the present invention described below. The MI monitor 266and the pacing energy level selector 268 can be implemented by software,firmware, or combinations thereof. It is also possible that all, orportions, of the MI monitor 266 and the pacing energy level selector 268can be implemented using hardware. Further, it is also possible thatall, or portions, of the MI monitor 266 and the pacing energy levelselector 268 can be implemented separate from the microcontroller 260.The monitor 266 and/or the selector 268 can communicate with theventricular evoked response monitor 263, or the MI monitor 266 and/orthe pacing energy level selector 268 can monitor ventricular evokedresponse metrics on their own. The MI monitor 266 can be used to performstep 312, discussed below with reference to FIG. 3. The pacing energylevel selector 268 can be used to perform at least some of the steps ofFIG. 4, which are discussed below.

The implantable device can also include a patient alert 219, whichproduces a vibratory or auditory alert, or the like, when triggered. Thepatient alert 219 can be triggered, e.g., at step 314, discussed belowwith reference to FIG. 3.

Still referring to FIG. 2, cardiac signals are also applied to theinputs of an analog-to-digital (ND) data acquisition system 290. Thedata acquisition system 290 is configured to acquire intracardiacelectrogram signals, convert the raw analog data into a digital signal,and store the digital signals for later processing and/or telemetrictransmission to an external device 202. The data acquisition system 290is coupled to the right atrial lead 120, the coronary sinus lead 124,and the right ventricular lead 130 through the switch 274 to samplecardiac signals across any pair of desired electrodes.

The data acquisition system 290 can be coupled to the microcontroller260, or other detection circuitry, for detecting an evoked response fromthe heart 112 in response to an applied stimulus, thereby aiding in thedetection of “capture”. Capture occurs when an electrical stimulusapplied to the heart is of sufficient energy to depolarize the cardiactissue, thereby causing the heart muscle to contract. Themicrocontroller 260 detects a depolarization signal during a windowfollowing a stimulation pulse, the presence of which indicates thatcapture has occurred. The microcontroller 260 enables capture detectionby triggering the ventricular pulse generator 272 to generate astimulation pulse, starting a capture detection window using the timingcontrol circuitry 279 within the microcontroller 260, and enabling thedata acquisition system 290 via control signal 292 to sample the cardiacsignal that falls in the capture detection window and, based on theamplitude, determines if capture has occurred.

The implementation of capture detection circuitry and algorithms arewell known. See for example, U.S. Pat. No. 4,729,376 (Decote, Jr.); U.S.Pat. No. 4,708,142 (Decote, Jr.); U.S. Pat. No. 4,686,988 (Sholder);U.S. Pat. No. 4,969,467 (Callaghan et. al.); and U.S. Pat. No. 5,350,410(Mann et. al.), which patents are hereby incorporated herein byreference. The type of capture detection system used is not critical tothe present invention.

The microcontroller 260 is further coupled to the memory 294 by asuitable data/address bus 296, wherein the programmable operatingparameters used by the microcontroller 260 are stored and modified, asrequired, in order to customize the operation of the implantable device110 to suit the needs of a particular patient. Such operating parametersdefine, for example, pacing pulse amplitude, pulse duration, electrodepolarity, rate, sensitivity, automatic features, arrhythmia detectioncriteria, and the amplitude, waveshape and vector of each shocking pulseto be delivered to the patient's heart 112 within each respective tierof therapy. The memory 294 can also be used to store information aboutventricular evoked response metrics and changes in the same can bedetected based on the stored information using embodiments of thepresent invention.

The operating parameters of the implantable device 110 may benon-invasively programmed into the memory 294 through a telemetrycircuit 201 in telemetric communication with an external device 202,such as a programmer, transtelephonic transceiver, or a diagnosticsystem analyzer. The telemetry circuit 201 can be activated by themicrocontroller 260 by a control signal 206. The telemetry circuit 201advantageously allows intracardiac electrograms and status informationrelating to the operation of the device 110 (as contained in themicrocontroller 260 or memory 294) to be sent to the external device 202through an established communication link 204. The telemetry circuit 201can also be used to trigger alarms or alerts of the external device 202,or to instruct the external device 202 to notify a caregiver regardingdetection of various episodes, occurrences and changes in conditionsthat are detected using embodiments of the present invention.

For examples of such devices, see U.S. Pat. No. 4,809,697, entitled“Interactive Programming and Diagnostic System for use with ImplantablePacemaker” (Causey, III et al.); U.S. Pat. No. 4,944,299, entitled “HighSpeed Digital Telemetry System for Implantable Device” (Silvian); andU.S. Pat. No. 6,275,734 entitled “Efficient Generation of SensingSignals in an Implantable Medical Device such as a Pacemaker or ICD”(McClure et al.), which patents are hereby incorporated herein byreference.

The implantable device 110 additionally includes a battery 211 whichprovides operating power to all of the circuits shown in FIG. 2. If theimplantable device 110 also employs shocking therapy, the battery 211should be capable of operating at low current drains for long periods oftime, and then be capable of providing high-current pulses (forcapacitor charging) when the patient requires a shock pulse. The battery211 should also have a predictable discharge characteristic so thatelective replacement time can be detected.

The implantable device 110 can also include a magnet detection circuitry(not shown), coupled to the microcontroller 260. It is the purpose ofthe magnet detection circuitry to detect when a magnet is placed overthe implantable device 110, which magnet may be used by a clinician toperform various test functions of the implantable device 110 and/or tosignal the microcontroller 260 that the external programmer 202 is inplace to receive or transmit data to the microcontroller 260 through thetelemetry circuits 201.

As further shown in FIG. 2, the device 110 is also shown as having animpedance measuring circuit 213 which is enabled by the microcontroller260 via a control signal 214. The known uses for an impedance measuringcircuit 213 include, but are not limited to, lead impedance surveillanceduring the acute and chronic phases for proper lead positioning ordislodgement; detecting operable electrodes and automatically switchingto an operable pair if dislodgement occurs; measuring respiration orminute ventilation; measuring thoracic impedance for determining shockthresholds and heart failure condition; detecting when the device hasbeen implanted; measuring stroke volume; and detecting the opening ofheart valves, etc. The impedance measuring circuit 213 is advantageouslycoupled to the switch 274 so that any desired electrode may be used. Theimpedance measuring circuit 213 is not critical to the present inventionand is shown only for completeness.

In the case where the implantable device 110 is also intended to operateas an implantable cardioverter/defibrillator (ICD) device, it mustdetect the occurrence of an arrhythmia, and automatically apply anappropriate electrical shock therapy to the heart aimed at terminatingthe detected arrhythmia. To this end, the microcontroller 260 furthercontrols a shocking circuit 216 by way of a control signal 218. Theshocking circuit 216 generates shocking pulses of low (up to 0.5Joules), moderate (0.5-10 Joules), or high energy (11 to 40 Joules), ascontrolled by the microcontroller 260. Such shocking pulses are appliedto the patient's heart 112 through at least two shocking electrodes, andas shown in this embodiment, selected from the left atrial coilelectrode 228, the RV coil electrode 236, and/or the SVC coil electrode238. As noted above, the housing 240 may act as an active electrode incombination with the RV electrode 236, or as part of a split electricalvector using the SVC coil electrode 238 or the left atrial coilelectrode 228 (i.e., using the RV electrode as a common electrode).

The above described implantable device 110 was described as an exemplarypacing device. One or ordinary skill in the art would understand thatembodiments of the present invention can be used with alternative typesof implantable devices. Accordingly, embodiments of the presentinvention should not be limited to use only with the above describeddevice.

Ventricular Automatic Capture Threshold Detection

The success of a cardiac pacemaker in depolarizing or “capturing” theheart relies on the pacing stimulus energy level delivered to themyocardium exceeding a threshold value, known as the capture threshold.More specifically, the capture threshold represents the amount ofelectrical energy required to alter the permeability of the myocardialcells to thereby initiate cell depolarization. If the energy of thepacing stimulus does not exceed the capture threshold, then thepermeability of the myocardial cells will not be altered and thus nodepolarization will result. In contrast, if the energy of the pacingstimulus exceeds the capture threshold, then the permeability of themyocardial cells will be altered such that depolarization will result.The energy is a function of current, voltage and pulse duration (time).Accordingly, the pacing energy level can be adjusted by adjusting one ofmore of current, voltage and pulse duration.

The capture threshold is not fixed, but rather, may increase anddecrease during of the course of a single day, on a daily basis, as wellas in response to changes in cardiac disease status. Changes in thecapture threshold may be detected by monitoring the efficacy ofstimulating pulses at a given energy level. If capture does not occur ata particular stimulation energy level which previously was adequate toeffect capture, then it can be surmised that the capture threshold hasincreased and that the stimulation energy should be increased. Incontrast, if capture occurs consistently at a particular stimulationenergy level over a relatively large number of successive stimulationcycles, then it is possible that the capture threshold has decreasedsuch that the stimulation energy is being delivered at level higher thannecessary to effect capture. This can be checked by lowering thestimulation energy level and monitoring for capture, or loss of thereof,at the new lower energy level.

To reduce current drain on the power supply, it is desirable toautomatically adjust the pacemaker such that the amount of stimulationenergy delivered to the myocardium is maintained at a level that willreliably capture the heart without wasting power. Such a process hasbeen called many things, including automatic capture thresholddetection, automatic stimulation threshold search, automatic captureverification, automatic verification of capture, and Autocapture™. Forthe following discussion, this process will be referred to as automaticcapture threshold detection.

While there are certainly variations in how and when automatic capturethreshold detection can be performed, they all have a similar goal,which is generally to determine whether a delivered pacing stimulusresults in stimulation of the myocardium, and, consequently, to adaptthe stimulation pulses to a level somewhat above (e.g., a margin above)that which is needed to maintain capture.

Automatic capture threshold detection can be performed when a device isimplanted, and from time to time thereafter so that pacing stimulationlevels are appropriately adjusted as patient conditions change. Forexample, an automatic capture threshold detection algorithm can beperformed whenever two consecutive pacing pulses fail to evoke capture,and/or may be performed periodically (e.g., every 8 hours, every 24hours, etc). The following patents, each of which are incorporatedherein by reference, provide details of various exemplary automaticventricular capture threshold detection algorithms: U.S. Pat. No.7,400,923 (Levine) entitled “Multi-chamber ventricular automatic capturemethod and apparatus for minimizing true and blanking period inducedventricular undersensing”; U.S. Pat. No. 6,345,201 (Sloman et al.)entitled “System and method for ventricular capture using far-fieldevoked response.”

Depending on the pacing mode that is being used, automatic capturethreshold detection can be performed in the atrium and/or in theventricles. When performed in an atrium, this process can be referred tomore specifically as atrial automatic capture threshold detection.Similarly, when performed in a ventricle, this process can be referredto more specifically as ventricular automatic capture thresholddetection.

When ventricular automatic capture threshold detection is beingperformed, the implantable cardiac device monitors for ventricularconduction (i.e., ventricular evoked response, also known as pacedR-waves or paced ventricular events) that occur in response toventricular pacing pulses. Specific embodiments of the present inventiontake advantage of this process by determining and storing informationabout (e.g., metrics of) the monitored ventricular evoked responses,such as, but not limited to ventricular evoked response peak-to-peakamplitude, ventricular evoked response area, ventricular evoked responsemaximum slope, ventricular evoked response maximum amplitude,ventricular evoked response minimum amplitude, ventricular evokedresponse timing, and/or the dispersion of any of the aforementionedmetrics, and use such stored information to monitor levels of BNP and/orperform HF and/or MI monitor based on the monitored levels of BNP. Inother words, whenever (or at least some of the times that) a ventricularautomatic capture threshold detection process is being performed, one ormore ventricular evoked response metric can be measured and stored, andthereafter used for monitoring levels of BNP and/or performing HF and/orMI monitoring based on the monitored levels of BNP. In this manner,specific embodiments of the present invention take advantage of the factthat the ventricular automatic capture threshold detection process willoccur from time to time by learning additional information during suchprocess.

B-type Natriuretic Peptide (BNP) Monitoring

The high level flow diagram of FIG. 3 will now be used to describemethods for use by an implanted system including an implanted cardiacdevice and at least one implanted lead, for monitoring a patient's levelof BNP. Embodiments of the present invention are also directed tochronically implanted systems that can implement such methods.

Referring to FIG. 3, at step 302, at least one ventricle is paced for aperiod of time to provoke a ventricular evoked response. At step 304, aventricular intracardiac electrogram (IEGM) is obtained, which isindicative of the ventricular evoked response during the period of timethat the at least one ventricle is being paced. Steps 302 and 304 can beaccomplished using the implantable cardiac device 110 and the rightventricular lead 130, which were discussed above with reference to FIGS.1 and 2, but embodiments of the present invention should not be limitedthereto.

At step 306, based on the ventricular IEGM there is a determination ofventricular evoked response metric(s) indicative of ventricularelectrical activity during the period of time, and information aboutsuch ventricular evoked response metric(s) is stored, e.g., in memory294 of FIG. 2. Metrics of ventricular evoked response that can bemeasured from the ventricular IEGM, include, e.g., ventricular evokedresponse peak-to-peak amplitude, ventricular evoked response area,ventricular evoked response maximum slope, ventricular evoked responsemaximum amplitude (ventricular evoked response max), ventricular evokedresponse minimum amplitude (ventricular evoked response min),ventricular evoked response timing, and/or the dispersion of any of theaforementioned metrics. For example, ventricular evoked responsepeak-to-peak amplitude dispersion can be the difference between themaximum ventricular evoked response peak-to-peak amplitude and theminimum ventricular evoked response peak-to-peak amplitude (i.e., therange of peak-to-peak amplitudes). The dispersion of another one of theother above mentioned metrics can alternatively or additionally be used.Also, other measures of dispersion besides range can be used, e.g.,standard deviation, interquartile range, mean difference, medianabsolute deviation, average absolute deviation (or simply averagedeviation), coefficient of variation, quartile coefficient ofdispersion, relative mean difference, variance (the square of thestandard deviation) or variance-to-mean ratio. Step 306 can beperformed, e.g., by the ventricular evoked response monitor 263 of FIG.2, but is not limited thereto.

Preferably, the ventricular evoked response metric(s) that aredetermined at step 306, each time step 306 is repeated, is/are of thesame type, so that such metric(s) can be readily compared. For example,each time step 306 is performed a ventricular evoked responsepeak-to-peak amplitude and a ventricular evoked response area for 60cardiac cycles can be determined.

Preferably each period of time referred to in steps 302, 304 and 306spans a plurality of cardiac cycles, so that ventricular evoked responsemetric(s) is/are determined for each of a plurality of cardiac cycles,and metrics of the same type (e.g., ventricular evoked responsepeak-to-peak amplitude) are combined, e.g., averaged, summed, filtered(according to signal stability and/or quality), heart rate corrected, orthe like, to reduce the affects of noise and motion artifacts on suchmeasurements. For example, the ventricular evoked response peak-to-peakamplitude for 60 cardiac cycles can be measured and averaged to producethe ventricular evoked response peak-to-peak amplitude for a period oftime lasting 60 cardiac cycles. Additionally, or alternatively, aventricular evoked response area and/or ventricular evoked responsemaximum slope for the same 60 cardiac cycles can be measured andaveraged to produce the ventricular evoked response area and/or theventricular evoked response maximum slope. Accordingly, in this example,the result of step 306 can be a ventricular evoked response peak-to-peakamplitude, a ventricular evoked response area and/or a ventricularevoked response maximum slope, for the period of time (e.g., for aperiod of time lasting 60 cardiac cycles).

At step 308, the patient's level of BNP is estimated based on at leastone ventricular evoked response metric determined at step 306. This canbe accomplished, e.g., by plugging one or more ventricular evokedresponse metric (determined at step 306) into an algorithm or othermodel that converts such metrics to estimates of BNP. Such an algorithmor model can be determined during a calibration procedure during whichactual measures of BNP (e.g., from blood samples) and ventricular evokedresponse metric(s) are measured simultaneously. In accordance withspecific embodiments, a quadratic or higher order polynomial equationcan be used to estimate the patient's level of BNP. For example, thefollowing equation can be used:erBNP=k ₁*ER² +k ₂ER+b,

where

-   -   k₁, k₂, and b are constants determined from a quadratic fit,    -   ER is a measured ventricular evoked response metric, and    -   erBNP is the unknown level of BNP being estimated based on the        measured ventricular evoked response metric.

The above equation can also be expanded for use with various differenttypes of ventricular evoked response metrics.

In accordance with an embodiment of the present invention, a calibration(e.g., an initial calibration) can be performed using the followingequation

${erBNP} = {{\left( \frac{{highBNP} - {lowBNP}}{{highER} - {lowER}} \right)\left( {{ER} - {highER}} \right)} + {highBNP}}$

where

-   -   erBNP is the unknown level of BNP whose value is being        estimated,    -   ER is the ventricular evoked response metric corresponding to        the unknown level of BNP,    -   highBNP is a high measured BNP level,    -   lowBNP is a low measured BNP level,    -   highER is the ventricular evoked response metric corresponding        to the highBNP, and    -   lowER is the ventricular evoked response metric corresponding to        the lowBNP.

The high measured BNP level (i.e., highBNP) and the ventricular evokedresponse metric corresponding to the highBNP (i.e., highER) can bemeasured, e.g., when a patient is initially admitted to a hospital for acondition that corresponds to a high BNP level (e.g., an HF exacerbationor an acute MI). The low measured BNP level (i.e., lowBNP) and theventricular evoked response metric corresponding to the lowBNP (i.e.,lowER) can be measured, e.g., post-treatment for the condition, butprior to discharge. The highBNP and lowBNP values can be measured fromblood samples take from the patient, e.g., using a Triage™ BNP Testavailable from Biosite Inc. of San Diego, Calif., or using an i-STATAnalyzer™ and BNP Cartridge available from Abbott Laboratories of AbbottPark, Ill., but not limited thereto. The highER and lowER metrics can bemeasured using the cardiac device implanted within the patient, i.e.,the same device that can thereafter be used to estimate a value of thelevel of BNP based on ventricular evoked response metric(s).

Steps 302, 304 and 306 can be repeated from time to time, as indicatedby arrow 307 (or arrow 309). In other words, steps 302, 304 and 306 canbe performed for each of a plurality of periods of time. For examples,steps 302, 304 and 306 can be performed for 60 seconds or 60 cardiaccycles, and repeated every 10 minutes, hour, day, or the like. Each timesteps 302, 304 and 306 are preformed, a patient's level of BNP can bemonitored (e.g., a value estimated) at step 308. As these steps arerepeated, changes in the patient's level of BNP can be monitored basedon the changes in the levels of BNP estimated at step 308. Step 308 canbe performed, e.g., by the BNP monitor 264 of FIG. 2, but is not limitedthereto.

Levels of BNP need not be estimated at step 308, but rather, as steps302, 304 and 306 are repeated from time to time, changes in the levelsof BNP can be monitored at step 308 based on the changes in themetric(s) of ventricular evoked response determined at step 306. Forexample, if it is determined that there is a positive correlationbetween a specific metric of ventricular evoked response and level ofBNP, if that metric increases over time, then at step 308 there can be adetermination that the level of BNP has increased over time. This isjust an example, which is not meant to be limiting.

In specific embodiments, steps 302, 304 and 306 (and optionally step308) are only performed when certain pre-conditions are satisfied, e.g.,there is consistent capture, there is a specific pacing rate, specificpacing energy level, specific patient posture and/or the patient is atrest. Additional and/or alternative pre-conditions are also possible,and within the scope of the present disclosure. In such embodiments, thedevice can be programmed to periodically perform these steps to (e.g.,every four hours), but only if the pre-conditions are satisfied. If thepre-conditions are not satisfied, the device can wait until they aresatisfied to perform the steps, or the device can skip the performing ofthe steps. By only determining levels of BNP (and/or changes therein)when certain pre-conditions are satisfied, there is a good chance thatdetected changes in BNP are not simply due to changes in such conditions(e.g., due to changes in pacing rate and/or pacing energy level).

Whenever steps 302, 304 and 306 are preformed, a patient's level of BNPcan be determined at step 308. Alternatively, as mentioned above, steps302, 304 and 306 may be performed multiple times before step 308 isperformed (e.g., in which case, changes in a patient's level of BNP maybe determined at step 308). For example, at step 308, a change in the atleast one ventricular evoked response metric over time can be detectedbased on the information stored at various instances of step 306. Such achange can be an increase, a decrease, or there can be relatively nochange. A magnitude of the change can also be determined. For example,at step 308 a ventricular evoked response peak-to-peak amplitude for asecond period of time can be compared to a ventricular evoked responsepeak-to-peak amplitude for a first period of time. Additionally, oralternatively, a ventricular evoked response area for the second periodof time can be compared to the ventricular evoked response area for thefirst period of time. Where multiple ventricular evoked response metricsare to be compared at step 308, weighting factors can be used to combinethe ventricular evoked response metrics or combine the results ofmultiple comparisons.

At step 308, a change in a patient's level of BNP can be monitored basedon the detected change in the at least one ventricular evoked responseover time. Step 308 can include determining whether a patient's level ofBNP has increased, decreased, or stayed relatively the same. This caninclude interpreting an increase in a certain ventricular evokedresponse metric, such as ventricular evoked response peak-to-peakamplitude and/or ventricular evoked response area, as being indicativeof increased level of BNP, and interpreting decreases in the sameventricular evoked response metric as being indicative of decreases inlevel of BNP. Relatively no change in a ventricular evoked responsemetric can be interpreted in relatively no change in level of BNP.Alternative ventricular evoked response metrics may be used. How tointerpret increases or decreases in alternative ventricular evokedresponse metrics depends on the metric, and can be determined throughexperimentation, e.g., from empirical data. For example, someventricular evoked response metrics (such a ventricular evoked responsepeak-to-peak amplitude) have a positive correlation with level of BNP,while others have a negative correlation.

HF Monitoring

As described above in the Background, chronic diseases such as CHFrequire close medical management to reduce morbidity and mortality.However, the conventional approach of periodic patient follow-ups hasproved unsatisfactory, as life-threatening exacerbations can developbetween physician follow-up examinations. Further, if a developing HFexacerbation is recognized early, it can be more easily andinexpensively terminated, typically with a modest increase in oraldiuretic. However, if it develops beyond the initial phase, an acute HFexacerbation becomes difficult to control and terminate. Hospitalizationin an intensive care unit is often required. It is during an acuteexacerbation of heart failure that many patients succumb to the disease.

Further, it is often difficult for patients to recognize a developing HFexacerbation, despite the presence of numerous physical signs that wouldallow a physician to readily detect it. Furthermore, since exacerbationstypically develop over hours to days, even frequently scheduled routinefollow-up with a physician cannot effectively detect most developingexacerbations. It is therefore desirable to have a system that allowsfor routine, frequent monitoring of patients so that an exacerbation canbe recognized early in its course. With the patient and/or physicianthus notified by the monitoring system of the need for medicalintervention, a developing exacerbation can more easily andinexpensively be terminated early in its course.

As indicated at step 310, a patient's HF condition can be monitoredbased on the patient's level of BNP monitored at step 308. This caninclude interpreting an increase in a patient's level of BNP as beingindicative of a worsening HF condition and/or an increased risk of anacute HF exacerbation, and interpreting decreases in the patient's levelof BNP as being indicative of an improved HF condition and/or a reducedrisk of an acute HF exacerbation. Relatively no change in the patient'slevel of BNP can be interpreted as relatively no change in the HFcondition and/or relatively no change in the risk of an acute HFexacerbation. The term “based on”, as used herein, means based at leastin part on (unless otherwise specified), meaning that other factors canbe used in a determination or decision. For example, the patient's HFcondition can be monitored based on the patient's level of BNP, as wellas on (e.g., in combination with) other factors or determinations.

Additionally, or alternatively, step 310 can include predicting animpending acute HF exacerbation based on whether the estimated level ofBNP exceeds a first threshold, and/or whether the estimated level of BNPexceeds a second threshold can be used to detect an acute HFexacerbation. The term “impending” can mean, e.g., within a month, butis not limited thereto. The first threshold and the second threshold,may or may not be the same. The threshold(s) can be set as a percentageof the patient's high BNP value, e.g., 80% of the high BNP value. Suchthresholds can be determined, e.g., using empirical data collected overtime for the patient and/or for a patient population, but is not limitedthereto. As will be described below, with reference to step 314, anappropriate response can be triggered when an impending acute HFexacerbation is predicted and/or an acute HF exacerbation is detected.

At step 314, a response can be triggered if an estimated value for thepatient's level of BNP (an increase in the patient's level of BNP)exceeds a specified threshold. Alternatively, or additionally, at step314 a response can be triggered if a change in the at least oneventricular evoked response metric is in a direction indicative of anincrease in the patient's level of BNP beyond a specified threshold.

If it is determined at step 310 that the patient's level of BNP hasincreased beyond a specified threshold (and thus, e.g., that a patienthas a heightened risk of an acute HF exacerbation, and/or that thepatient's HF condition has worsened beyond a specified threshold, or itis believed that an acute HF exacerbation has been detected), then atstep 314 an appropriate therapy can be triggered. One type of therapywould be for an implanted device, if appropriately equipped, to deliverappropriate drug therapy. In another embodiment, the implantable devicecan perform appropriate pacing therapy to attempt to prevent and/ortreat an acute heart failure exacerbation. One of ordinary skill in theart would understand from the above description that other responses arealso possible, while still being within the spirit and scope of thepresent invention.

Additionally or alternatively, a patient can be alerted (e.g., usingalert 219) at step 314 if it was determined at step 310 that thepatient's level of BNP exceeded a specific threshold (and thus, e.g.,that a patient has a heightened risk of an acute HF exacerbation, and/orthat the patient's HF condition has worsened beyond a specifiedthreshold, or it is believed that an acute HF exacerbation has beendetected). An alert could be a vibratory or auditory alert thatoriginates from within the implantable device 110. Alternatively, theimplantable device 110 may wirelessly transmit an alert to an externaldevice (e.g., 202) that produces a visual or auditory alert that apatient can see or hear. The alert may inform that patient that heshould rest, or if the patient is operating some type of dangerousmachinery (e.g., a car), that the patient should stop what they aredoing. By alerting the patient to rest, it is possible an HFexacerbation may be avoided, or if it does occur, the patient will beless dangerous to themselves and others if the patient is resting whenthe exacerbation occurs (as opposed, e.g., to driving a car). It is alsopossible that the alert can be generated by an external device (e.g.,202).

Additionally or alternatively, the patient can be instructed to takemedication when alerted. Additionally or alternatively, a caregiver(e.g., physician) can be alerted if it is determined that the patient'slevel of BNP, or an increase therein, beyond a threshold (and thus,e.g., that a patient has a heightened risk of an acute HF exacerbation,and/or that the patient's HF condition has worsened beyond a specifiedthreshold and/or that it is believed that an acute HF exacerbation hasbeen detected). Additionally or alternatively, information related toventricular evoked response metric(s) and/or changes therein can bestored. This can include, for example, storing information related toventricular evoked response peak-to-peak amplitude, ventricular evokedresponse area and/or ventricular evoked response maximum slope, but isnot limited thereto. Additionally, or alternatively, estimated values oflevels of BNP can be stored. If such information is stored in animplanted device, such information can be continually, or from time totime, automatically uploaded to an external device (e.g., 202). Such anexternal device 202 can be located, e.g., in the patient's home, and theinformation can be transmitted (e.g., through telephone lines or theInternet) to a medical facility where a physician can analyze theinformation. For example, the external device 202 can be a bedsidemonitor, or an ambulatory device that the patient carries with them.Alternatively, the external device 202 can be an external programmerlocated at a medical facility, and the information can be uploaded whenthe patient visits the facility.

MI Monitoring

As described above in the Background, there are numerous reasons why itwould be useful if systems and methods were available for chronicallymonitoring for acute MIs, and risks thereof.

As indicated at step 312, acute MI monitoring can be performed based onthe patient's level of BNP monitored at step 308. This can includeinterpreting an increase in a patient's level of BNP as being indicativeof an increased risk of an acute MI, and interpreting decreases in thepatient's level of BNP as being indicative of a reduced risk of an acuteMI. Relatively no change in the patient's level of BNP can beinterpreted in relatively no change in the risk of an acute MI.

Additionally, or alternatively, step 312 can include predicting animpending acute MI based on whether the estimated level of BNP exceeds afirst threshold, and/or whether the estimated level of BNP exceeds asecond threshold can be used to detect an acute MI occurrence. The term“impending” can mean, e.g., within a month, but is not limited thereto.The first threshold and the second thresholds, may or may not be thesame. The threshold(s) can be set as a percentage of the patient's highBNP value, e.g., 75% of the high BNP value. Such thresholds can bedetermined, e.g., using empirical data collected over time for thepatient and/or for a patient population, but is not limited thereto. Aswill be described below, with reference to step 314, an appropriateresponse can be triggered when an impending acute MI is predicted and/oran acute MI is detected.

If it is determined at step 312 that the patient's level of BNP hasincreased beyond a specified threshold (and thus, e.g., that a patienthas a heightened risk of an acute MI and/or that an impending acute MIis predicted, or it is believed that an acute MI has been detected),then at step 314 an appropriate therapy can be triggered. One type oftherapy would be for an implanted device, if appropriately equipped, todeliver appropriate drug therapy. In another embodiment, the implantabledevice can perform appropriate pacing therapy to attempt to treat anacute MI. One of ordinary skill in the art would understand from theabove description that other responses are also possible, while stillbeing within the spirit and scope of the present invention.

Additionally or alternatively, a patient can be alerted (e.g., usingalert 219) at step 314 if it was determined at step 310 that thepatient's level of BNP exceeded a specific threshold (and thus, e.g.,that there is a detection of a heightened risk of an acute MI and/orthat an impending acute MI is predicted, or it is believed that an acuteMI has been detected). An alert could be a vibratory or auditory alertthat originates from within the implantable device 110. Alternatively,the implantable device 110 may wirelessly transmit an alert to anexternal device (e.g., 202) that produces a visual or auditory alertthat a patient can see or hear. The alert may inform that patient thathe should rest, or if the patient is operating some type of dangerousmachinery (e.g., a car), that the patient should stop what they aredoing. By alerting the patient to rest, the patient will be lessdangerous to themselves and others if the patient is resting when theacute MI occurs (as opposed, e.g., to driving a car). It is alsopossible that the alert can be generated by an external device (e.g.,202).

Additionally or alternatively, the patient can be instructed to takemedication when alerted. Additionally or alternatively, a caregiver(e.g., physician) can be alerted if it is determined that the patient'slevel of BNP, or an increase therein, beyond a threshold (and thus,e.g., that there is a detection of a heightened risk of an acute MIand/or that an impending acute MI is predicted, or it is believed thatan acute MI has been detected). Additionally or alternatively,information related to ventricular evoked response metric(s) and/orchanges therein can be stored. This can include, for example, storinginformation related to ventricular evoked response peak-to-peakamplitude, ventricular evoked response area and/or ventricular evokedresponse maximum slope, but is not limited thereto. Additionally, oralternatively, estimated values of levels of BNP can be stored. If suchinformation is stored in an implanted device, such information can becontinually, or from time to time, automatically uploaded to an externaldevice (e.g., 202). Such an external device 202 can be located, e.g., inthe patient's home, and the information can be transmitted (e.g.,through telephone lines or the Internet) to a medical facility where aphysician can analyze the information. For example, the external device202 can be a bedside monitor, or an ambulatory device that the patientcarries with them. Alternatively, the external device 202 can be anexternal programmer located at a medical facility, and the informationcan be uploaded when the patient visits the facility.

Ventricular Pacing Energy Level

Specific embodiments of the present invention relate to selecting apreferred ventricular pacing energy level. As briefly discussed above, agoal of ventricular automatic capture threshold detection is to adjustthe stimulation energy delivered to a ventricle so that it is at a levelthat will reliably capture the ventricle without wasting energy. This istypically accomplished by determining, from time to time, theventricular capture threshold level and pacing the ventricle at a levelequal to the ventricular capture threshold level, or more likely, equalto the ventricular capture threshold level plus a specified margin,e.g., a safety margin or working margin. A safety margin can be defined,e.g., as a ratio (e.g., 2:1 or 3:1) or percentage (e.g., 150% or 200%)relative to the measured ventricular capture threshold. A working margincan be defined, e.g., as a fixed amount (e.g., 0.25V) added to themeasured ventricular capture threshold. Typically, a device will pace aventricle at the capture threshold plus the specified margin, not takinginto account other factors. In contrast, in accordance with theembodiments of the present invention described with reference to FIG. 4,ventricular pacing may occur at a somewhat higher level if the result isa reduction in the patient's level of BNP, an improved HF condition, areduced risk of an HF exacerbation, and/or a reduced risk of an acuteMI.

Referring to FIG. 4, at a step 402, a ventricular capture threshold forpacing in a ventricle is determined using at least one implanted lead.As explained above, the ventricular capture threshold represents theamount of electrical energy required to cause ventriculardepolarization. There are various well known ways to determine theventricular capture threshold, and thus, this step need not be describedin additional detail.

At step 404, a first ventricular pacing energy level that provides forreliable capture of a ventricle is determined based on the ventricularcapture threshold determined at step 402. As was discussed above, thisenergy level can be the ventricular capture threshold level, or theventricular capture threshold level plus a specified margin, e.g., asafety or working margin.

At step 406, at least one ventricular evoked response metric isdetermined for one or more ventricular evoked response (also known as apaced ventricular event) that occurs in response to ventricular pacingat a first energy level specified based on the determined ventricularcapture threshold. As was discussed above with reference to FIG. 3,exemplary ventricular evoked response metrics that can be measuredinclude ventricular evoked response maximum amplitude, ventricularevoked response minimum amplitude, ventricular evoked responsepeak-to-peak amplitude, ventricular evoked response duration,ventricular evoked response area, ventricular evoked response maximumslope, and ventricular evoked response timing, and/or the dispersion ofany of the aforementioned metric. Preferably such ventricular evokedresponse metric(s) is/are determined for a plurality of pacedventricular events that occurs in response to ventricular pacing at thefirst ventricular pacing energy level, and the metrics are combined,e.g., averaged, summed, or the like, to reduce the affects of noise andmotion artifacts on such measurements.

At step 408, at least one ventricular evoked response metric isdetermined for one or more ventricular evoked response (also known as apaced ventricular event) that occurs in response to ventricular pacingat one or more energy level greater than the first ventricular pacingenergy level. For example, the one or more energy level (greater thanthe first ventricular pacing energy level) can be one or more percentageof the first ventricular pacing energy level (e.g., 110%, 120% and 130%of the first ventricular pacing energy level), or one or more fixedvoltage level above the first ventricular pacing energy level (e.g.,0.25V, 0.50V and 0.75V). These are just a few examples, which are notmeant to be limiting.

The determining of the at least one ventricular evoked response metricat step 406 can occur during the determining of the ventricular capturethreshold at step 402, e.g., if energy levels above the actual capturethreshold are tested during the search for the ventricular capturethreshold. Similarly, the determining of the at least one ventricularevoked response metric at step 408 can occur during the determining ofthe ventricular capture threshold at step 402, e.g., if energy levelsabove the actual capture threshold and above the first ventricularpacing energy level are also tested during the search for theventricular capture threshold.

At step 410, a preferred ventricular pacing energy level to use forventricular pacing is determined (e.g., selected) based on theventricular evoked response metrics determined at steps 406 and 408. Atstep 410 a ventricular pacing energy level greater than the firstventricular pacing energy level (determined at step 404) can be selectedas the preferred ventricular pacing energy level, if it is determinedbased on ventricular evoked response metrics (determined at step 406 and408) that pacing at an energy level greater than the first ventricularpacing energy level would reduce the patient's level of BNP, improve thepatient's HF condition and/or reduce the patient's risk of an HFexacerbation and/or reduce the patient's risk of acute MI. Exemplarytechniques for determining the patient's level of BNP, HF conditionand/or risk of acute HF exacerbation and/or risk of acute MI based onlevels of BNP determined from ventricular evoked response metric(s) werediscussed above with reference to FIG. 3.

In the embodiment of FIG. 4, a pacing energy level that is higher thanis necessary for reliable capture may be selected if the higher energylevel provides for a reduction in level of BNP, an improved HF conditionand/or a lower risk of an acute HF exacerbation and/or a lower risk ofan acute MI. The extent of the reduction in the patient's level of BNP,the improvement in HF condition and/or the extent of the reduction inrisk of an acute HF exacerbation and/or the extent of the reduction inrisk of an acute MI can be used to determine whether it's worthincreasing the pacing energy level, because the higher the pacing energylevel the shorter the battery life. Various algorithms can be developedthat enable a cardiac device to make such decisions, e.g., based onprogrammed preferences of a physician. Alternatively, a physician canmake such a determination.

The present invention has been described above with the aid offunctional building blocks illustrating the performance of specifiedfunctions and relationships thereof. The boundaries of these functionalbuilding blocks have often been arbitrarily defined herein for theconvenience of the description. Alternate boundaries can be defined solong as the specified functions and relationships thereof areappropriately performed. Any such alternate boundaries are thus withinthe scope and spirit of the claimed invention. For example, it would bepossible to combine or separate some of the steps shown in FIGS. withoutsubstantially changing the overall events and results.

The previous description of the preferred embodiments is provided toenable any person skilled in the art to make or use the embodiments ofthe present invention. While the invention has been particularly shownand described with reference to preferred embodiments thereof, it willbe understood by those skilled in the art that various changes in formand details may be made therein without departing from the spirit andscope of the invention.

What is claimed is:
 1. A method for selecting a preferred ventricularpacing energy level, for use by an implanted system including animplanted cardiac device and at least one implanted lead, the methodcomprising: (a) determining a ventricular capture threshold for pacing aventricle using an implanted lead; (b) determining, using theventricular capture threshold, a first ventricular pacing energy levelthat provides for reliable capture of the ventricle; (c) pacing theventricle at the first ventricular pacing energy level to provoke atleast a first ventricular evoked response; (d) determining at least afirst ventricular evoked response metric for the at least firstventricular evoked response; (e) pacing the ventricle at a at leastsecond ventricular pacing energy level that is greater than the firstventricular pacing energy level and higher than is necessary forreliable capture of the ventricle to provoke at least a secondventricular evoked response; (f) determining at least a secondventricular evoked response metric for the at least second ventricularevoked response; (g) using the at least first and second ventricularevoked response metrics determined at (d) and (f) to determine whetherthe at least second ventricular pacing energy level provides a reductionin a patient's estimated level of B-type natriuretic peptide (BNP)compared to the first ventricular pacing energy level, (h) selecting thesecond ventricular pacing enemy level as the preferred ventricularpacing energy level, when the second ventricular pacing energy levelprovides a reduction in the patient's estimated level of B-typenatriuretic peptide (BNP) compared to the first ventricular pacing enemylevel.
 2. The method of claim 1, wherein step (b) comprises determiningthe first ventricular pacing energy level by adding a safety margin, aworking margin or some other margin to the ventricular capture thresholddetermined at step (a).
 3. The method of claim 1, wherein a measurementfor determining the at least first ventricular evoked response metric atstep (d) and/or a measurement for determining the at least secondventricular evoked response metric at step (f), occur during thedetermining of the ventricular capture threshold at step (a).
 4. Themethod of claim 1 wherein step (g) comprises: determining an estimatedfirst level of BNP using the at least first ventricular evoked responsemetric for the at least first ventricular evoked response that occurs inresponse to ventricular pacing at the first ventricular pacing energylevel; determining at least an estimated second level of BNP using theat least second ventricular evoked response metric for the at leastsecond ventricular evoked response that occurs in response toventricular pacing at the at least second ventricular pacing energylevel; and using the estimated levels of BNP to determine at least oneof: the patient's estimated level of BNP, HF condition, risk of acute HFexacerbation and risk of acute MI, at the first and the at least secondventricular pacing energy levels.
 5. The method of claim 4, furthercomprising (i) determining the extent of the reduction of at least oneof: the patient's estimated level of BNP, HF condition, risk of acute HFexacerbation and risk of acute MI, at the at least second ventricularpacing energy level compared to the first ventricular pacing energylevel.
 6. The method of claim 1, wherein the ventricular evoked responsemetrics determined at steps (d) and/or (f) are determined for aplurality of ventricular evoked responses.
 7. The method of claim 1,wherein the ventricular evoked response metrics determined at steps (d)and/or (f) are at least one of: a ventricular evoked responsepeak-to-peak amplitude, a ventricular evoked response area, and aventricular evoked response maximum slope.
 8. The method of claim 1,wherein the one or more ventricular evoked response metrics determinedat steps (d) and/or (f) are at least one of: a ventricular evokedresponse maximum amplitude, ventricular evoked response minimumamplitude, and a ventricular evoked response timing.
 9. The method ofclaim 4, wherein the ventricular evoked response metrics determined atsteps (d) and/or (f) are determined for a plurality of ventricularevoked responses, the metrics comprise a plurality of types of metrics,and metrics of the same type are combined at steps (d) and/or (f). 10.The method of claim 4, wherein the steps of estimating the first and atleast second levels of BNP at step (g) include: determining aventricular evoked response metric (lowER) while a patient has a lowlevel of BNP (lowBNP); determining a ventricular evoked response metric(highER) while the patient has a high level of BNP; and the estimatedfirst and at least second levels of BNP are estimated using thefollowing equation:${erBNP} = {{\left( \frac{{highBNP} - {lowBNP}}{{highER} - {lowER}} \right)\left( {{ER} - {highER}} \right)} + {highBNP}}$where erBNP is the unknown level of BNP, the value of which is beingestimated, ER is the ventricular evoked response metric corresponding tothe unknown level of BNP, the value of which is being estimated, highBNPis a high measured BNP level, lowBNP is a low measured BNP level, highERis the ventricular evoked response metric corresponding to the highBNP,and lowER is the ventricular evoked response metric corresponding to thelowBNP.
 11. A method for selecting a preferred ventricular pacing energylevel comprising: (a) determining a ventricular capture threshold forpacing a ventricle using an implanted lead; (b) determining, using theventricular capture threshold, a first ventricular pacing energy levelthat provides for reliable capture of the ventricle; (c) pacing theventricle at the first ventricular pacing energy level to provoke a atleast first ventricular evoked response; (d) determining at least afirst ventricular evoked response metric for the at least firstventricular evoked response that occurs in response to ventricularpacing at the first ventricular pacing energy level; (e) pacing theventricle at a at least second ventricular pacing energy level that isgreater than the first ventricular pacing energy level and higher thanis necessary for reliable capture of the ventricle to provoke at least asecond ventricular evoked response; (f) determining at least a secondventricular evoked response metric for the at least second ventricularevoked response that occurs in response to ventricular pacing at the atleast second ventricular pacing energy level; (g) determining a firstestimated level of B-type natriuretic peptide (BNP) based at least onthe first ventricular evoked response metric; (h) determining a secondestimated level of BNP based at least on the second ventricular evokedresponse metric; (i) comparing at least the first and second estimatedlevels of BNP determined at (g) and (h); and (j) selecting the secondventricular pacing energy level as the preferred ventricular pacingenergy level to use for ventricular pacing when the second ventricularpacing energy level results in a lower estimated level of BNP.
 12. Themethod of claim 11, wherein step (b) comprises determining the firstventricular pacing energy level by adding a safety margin, a workingmargin or some other margin to the ventricular capture thresholddetermined at step (a).
 13. The method of claim 11, wherein ameasurement for determining the at least first ventricular evokedresponse metric at step (d) and/or a measurement for determining the atleast second ventricular evoked response metric at step (f), occurduring the determining of the ventricular capture threshold at step (a).14. The method of claim 11, wherein step (j) includes: selecting thesecond ventricular pacing energy level as the preferred ventricularpacing energy level, when the comparison of step (i) indicates that thesecond ventricular pacing energy level would provide at least one of thefollowing: a reduction in a patient's estimated level of BNP, animproved heart failure (HF) condition, a reduction in the patient's riskof an acute HF exacerbation, and a reduction in the patient's risk of anacute myocardial infarction (MI).
 15. The method of claim 11, whereinstep (i) includes determining the extent of the reduction of at leastone of: a patient's estimated level of BNP, HF condition, risk of acuteHF exacerbation and risk of acute MI.
 16. The method of claim 11,wherein the ventricular evoked response metrics determined at steps (d)and/or (f) are determined for a plurality of ventricular evokedresponses.
 17. The method of claim 11, wherein the one or moreventricular evoked response metrics determined at steps (d) and/or (f)are at least one of: a ventricular evoked response peak-to-peakamplitude, a ventricular evoked response area, and a ventricular evokedresponse maximum slope.
 18. The method of claim 11, wherein the one ormore ventricular evoked response metrics determined at steps ((d) and/or(f) are at least one of: a ventricular evoked response maximumamplitude, ventricular evoked response minimum amplitude, and aventricular evoked response timing.
 19. The method of claim 11, whereinthe ventricular evoked response metrics determined at steps (d) and/or(f) are determined for a plurality of ventricular evoked responses, themetrics comprise a plurality of types of metrics, and metrics of thesame type are combined at steps (d) and/or (f).
 20. The method of claim11, wherein step (g) and (h) include: determining a ventricular evokedresponse metric (lowER) while a patient has a low level of BNP (lowBNP);determining a ventricular evoked response metric (highER) while thepatient has a high level of BNP; and the estimated first and at leastsecond levels of BNP are estimated using the following equation:${erBNP} = {{\left( \frac{{highBNP} - {lowBNP}}{{highER} - {lowER}} \right)\left( {{ER} - {highER}} \right)} + {highBNP}}$where erBNP is the unknown level of BNP, the value of which is beingestimated, ER is the ventricular evoked response metric corresponding tothe unknown level of BNP, the value of which is being estimated, highBNPis a high measured BNP level, lowBNP is a low measured BNP level, highERis the ventricular evoked response metric corresponding to the highBNP,and lowER is the ventricular evoked response metric corresponding to thelowBNP.